Results from the phase IIIb MabEase study: strong case made for rituximab SC in first-line DLBCL

In the November 2017 issue of Haematologica, Pieternella Lugtenburg of the Erasmus MC Cancer Institute in Rotterdam, Netherlands and colleagues published results from the MabEase phase IIIb clinical trial in first-line diffuse large B-cell lymphoma (DLBCL).  In this multicenter, randomized, open-label study, treatment-naïve patients with DLBCL were randomized 2:1 to receive either subcutaneous rituximab (intravenous 375 mg/m² cycle 1; subcutaneous 1,400 mg cycles 2–8) or intravenous rituximab (375 mg/m² cycles 1–8) plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 or 21 days (NCT01649856). The primary endpoint was investigator-assessed complete response (Cr)/unconfirmed complete response (CRu). Secondary endpoints included safety, treatment satisfaction, time savings, and survival. The objective of this study was to investigate the efficacy, safety and patient satisfaction of rituximab SC compared to the IV formulation as part of a rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen.

Key Highlights:

• Primary endpoint results indicated similar efficacy of the rituximab SC and IV formulations in the overall study population
• Similar safety profiles were observed in the SC and IV arms, with no new safety signals, and a rate of treatment-related deaths comparable with other reported studies
• Treatment satisfaction scores, as well as ‘impact on activities of daily living’ and ‘convenience’, were improved with SC compared to IV rituximab

Treatment:

• Total of 576 adult patients were randomized 2:1 and scheduled to receive eight cycles of rituximab in accordance with the prescribing information for rituximab in DLBCL
• n addition, patients received six to eight cycles of CHOP chemotherapy every 14 (CHOP-14) or 21 (CHOP-21) days
• The primary endpoint was investigator-assessed CR/CRu rate according to Cheson 1999 criteria at the end of induction (EOI) in the intent-to-treat (ITT) population
• Secondary endpoints included patient satisfaction measured by the Cancer Therapy Satisfaction Questionnaire (CTSQ) and Rituximab Administration Satisfaction Questionnaire (RASQ) and time savings; namely rituximab administration time, chair/bedtime, and hospital time
  • Other secondary endpoints were progression-free survival (PFS), event-free survival (EFS), disease-free survival (DFS), and overall survival (OS)

Efficacy:

• In the ITT population at EOI, CR/CRu rates (95% CI) were 50.6% and 42.4% in the SC and IV groups, respectively (P = 076)
• CR/CRu rates (95% CI) for all randomized patients were 45.7% for rituximab SC and 38.5% for IV, (P = 0.099).
  • When stratified by age, sex, BSA, CHOP regimen, and IPI score, statistically significantly higher CR/CRu rates were seen with SC treatment compared to IV in patients with low-intermediate IPI scores
• Median survival in the ITT population was not reached for PFS, EFS, DFS or OS
  • At 24 months of follow up, PFS was 75.0% in the SC group and 81.5% in the IV group (P = 0.175), and EFS was 68.6% and 73.4%, respectively (CI 95%, P = 0.456)

Safety:

• Safety profiles were similar between arms, with “no unexpected safety signals”
• Most AEs were grade 2 or 3 (339 [60.9%] of 557 patients in the safety population with cycle 2 dosing or beyond completed)
  • In cycle 2 or later (all patients received rituximab IV in cycle 1), 58.3% of SC and 54.3% of IV patients experienced at least one AE of grade ≥3
  • ARRs were reported in 20.9% of SC patients and 21.3% of IV patients on or after cycle 2
  • Ten patients (2.7%) receiving rituximab SC experienced an ARR of grade ≥3 on or after cycle 2, compared with nine patients (4.8%) receiving IV
• Injection site reactions were reported by 5.7% of patients receiving SC therapy; there were no such reactions with IV administration (P = 0.0002)
• In cycle 2 or later, 141 SC (38.2%) and 62 IV patients (33.0%) reported at least one SAE, most commonly febrile neutropenia (FN), neutropenia, and pneumonia
  • Higher proportion of patients experienced FN as an SAE in the SC the IV arm (11.7% vs. 6.4%, P = 0.0515), consistent with a higher incidence of grade 3/4 FN in the SC arm (12.5% vs. 6.9%, P = 0.0575)
• A similar proportion of patients in each group in the safety population discontinued rituximab treatment because of AEs (SC, 30 [8.1%]; IV, 19 [9.4%]), the most common of which were infections and infestations (2.4% and 2.5% of patients in the SC and IV groups, respectively; all treatment cycles)

Treatment Satisfaction:

• Mean RASQ scores for ‘impact on activities of daily living’, ‘convenience’, and ‘satisfaction’ were improved with SC compares to IV rituximab
• The mean RASQ scores were higher across all domains for rituximab SC IV, with mean satisfaction scores of 89.6 and 77.4 for the SC and IV groups, respectively
• When patients in the SC group were asked, “which treatment they would prefer, if given the option,” 90.8% stated a preference for SC over IV

The MabEase study achieved its goal of excluding major differences in efficacy and safety between rituximab SC and IV treatment arms in newly diagnosed DLBCL patients treated with R-CHOP. This has been underscored by the primary endpoint data which indicated similar efficacy of the rituximab SC and IV formulations in the overall study population. Of interest, the CR/CRu rates in this study (SC, 50.6%; IV, 42.4%) were lower compared to historical data, which may be attributed to the approximately 18% of patients discontinued study treatment before the end of cycle 8. However, among the SC and IV patients who did complete all eight cycles of induction, the CR/CRu rates were 57% and 47%, respectively. Despite the relatively lower CR rate, the overall response rate in this study was similar to observations in previous studies. In addition, similar safety profiles were observed in the SC and IV arms, no new safety signals, and a rate of treatment-related deaths that was comparable to those found in other studies. The most frequent SAE in this study was febrile neutropenia, although there was no difference between groups in rates of treatment discontinuation due to AEs or infections. Given that the MabEase study showed no major differences in efficacy and safety between treatment arms, coupled with higher RASQ scores in the rituximab SC arm, it’s rational to suggest that the results of this study support the use of rituximab SC in treatment-naïve patients with DLBCL.

Abstract

Intravenous rituximab plus chemotherapy is standard treatment for diffuse large B-cell lymphoma. A subcutaneous formulation of rituximab is expected to simplify and shorten drug preparation and administration, and to reduce treatment burden. MabEase (clinicaltrials.gov Identifier: 01649856) examined efficacy, safety and patient satisfaction with subcutaneous rituximab plus chemotherapy in treatment-naïve patients with diffuse large B-cell lymphoma. Patients were randomized 2:1 to subcutaneous rituximab (intravenous 375 mg/m cycle 1; subcutaneous 1,400 mg cycles 2–8) or intravenous rituximab (375 mg/m cycles 1–8) plus cyclophosphamide, doxorubicin, vincristine, and prednisone every 14 or 21 days. The primary endpoint was investigator-assessed complete response/unconfirmed complete response. Secondary endpoints included safety, treatment satisfaction (Cancer Treatment Satisfaction Questionnaire and Rituximab Administration Satisfaction Questionnaire), time savings, and survival. Of 576 randomized patients, 572 (378 subcutaneous; 194 intravenous) received treatment. End of induction complete response/unconfirmed complete response rates were 50.6% (subcutaneous) and 42.4% (intravenous). After a median 35 months, median overall, event-free and progression-free survivals were not reached. Grade ≥3 adverse events (subcutaneous 58.3%; intravenous 54.3%) and administration-related adverse events (both groups 21%) were similar between arms. Injection-site reactions were more common with subcutaneous injections (5.7% versus 0%, respectively). Rituximab Administration Satisfaction Questionnaire scores for ‘impact on activities of daily living’, ‘convenience’, and ‘satisfaction’ were improved with subcutaneous versus intravenous injections; Cancer Therapy Satisfaction Questionnaire scores were similar between arms. Median administration time (6 minutes vs. 2.6 to 3.0 hours), chair/bed and overall hospital times were shorter with subcutaneous versus intravenous rituximab. Overall, subcutaneous and intravenous rituximab had similar efficacy and safety, with improved patient satisfaction and time savings.